Process for preparing 2-phenyl-3-naphthylpropionic acid derivatives

ABSTRACT

A process for preparing a compound represented by general formulae (5) and (6) in the following reaction scheme or salts thereof, wherein R 1  represents a protective group for a nitrogen atom; R 2  represents a methanesulfonyl group or p-toluenesulfonyl group; R 3  represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X represents a halogen atom.  
                 
 
     The above process is useful as an industrial process for preparing intermediates of anticoagulant aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 208946/1993.

TECHNICAL FIELD

[0001] The present invention relates to a process for preparingintermediates of aromatic amidine derivatives which have anticoagulationaction based on excellent activated coagulation factor X (hereinafterabbreviated as FXa) inhibitory action and are described in JapanesePatent Application Laid-Open (kokai) No. 5-208946.

BACKGROUND ART

[0002] As intermediates of the aromatic amidine derivatives described inJapanese Patent Application Laid-Open (kokai) No. 5-208946, compounds ofthe following formulas (V), (Va), and (Vb), and salts thereof haveconventionally been known:

[0003] [wherein R¹ represents a protective group for a nitrogen atom andR³ represents a hydrogen atom, an aralkyl group, or an alkyl grouphaving 1 to 6 carbon atoms];

[0004] [wherein R¹ and R³ have the same meanings as described above];and

[0005] [wherein R¹ and R³ have the same meanings as described above].

[0006] Processes for preparing the above compounds are also described inthe cited publication.

[0007] A typical process for preparing these intermediates comprises thefollowing steps:

[0008] brominating 7-methyl-2-naphthalenecarbonitrile to thereby form7-bromomethyl-2-naphthalenecarbonitrile (first step);

[0009] further converting the 7-bromomethyl-2-naphthalenecarbonitrile toa phosphonium salt, [(7-cyano)-2-naphthyl)methyl]triphenylphosphoniumbromide (second step);

[0010] synthesizing ethyl2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxoacetateusing a Mitsunobu reaction of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate and(3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (third step);

[0011] subjecting the obtained ethyl2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxoacetateand the [(7-cyano)-2-nahpthyl)methyl]-triphenylphosphonium bromide to aWittig reaction (fourth step);

[0012] further performing catalytic hydrogenation to thereby formcompounds represented by formula (V) or (Va) (fifth step); and

[0013] dissolving compounds represented by formula (Va) in ethanol withheat, adding a small amount of sodium hydride thereto, and causingcrystallization while stirring the mixture at room temperature, tothereby obtain compounds represented by formula (Vb) (sixth step).

[0014] However, the above-described prior art process has the followingdrawbacks:

[0015] 1) bromination in the first step is performed intetrachloromethane, which is a suspected carcinogen;

[0016] 2) the product of the first step, i.e.,7-bromomethyl-2-naphthalenecarbonitrile, causes skin irritation whenisolated as crystals;

[0017] 3) comparatively expensive reagents, diethyl azodicarboxylate and1,8-diazabicyclo[5.4.0]-7-undecene, are used;

[0018] 4) by-products formed both in the third step and the fourth stepbehave as catalyst poisons in the catalytic hydrogenation of the fifthstep, and in order to remove the by-products, it requires purificationby silica gel column chromatography;

[0019] 5) palladium oxide monohydrate-barium sulfate, which is acatalyst of the catalytic hydrogenation, must be prepared upon use; and

[0020] 6) the yield of the sixth step is low and sodium hydride, whichinvolves a safety problem, is used.

[0021] Briefly, the prior art process is unsatisfactory as an industrialprocess.

[0022] Accordingly, an object of the present invention is to provide anindustrially satisfactory process for preparing compounds represented byformulas (V), (Va), and (Vb) and salts thereof, by use of safe,inexpensive, and easily available starting material(s) and auxiliarymaterial(s) and without a silica gel chromatographic purification step,as well as to provide an industrial process for preparing intermediatesof aromatic amidine derivatives which are described in Japanese PatentApplication Laid-Open (kokai) No. 5-208946.

DISCLOSURE OF THE INVENTION

[0023] In view of the foregoing, the present inventors have conductedearnest studies and have found

[0024] that halogenation can be effectively performed in an alkylnitrilesolvent in a first step, which permits the reaction to proceed to thenext step without isolation of the product;

[0025] that use of a pyrrolidinyloxyphenylacetic acid derivative,obtained through condensation of 4-hydroxyphenylacetic acids andsulfonyloxypyrrolidines, as one starting material provides a compoundrepresented by formula (V) or (Va) without requiring reaction to form aphosphonium salt and catalytic hydrogenation, and further without needfor preparation of an expensive reagent or a reagent required upon use;and

[0026] that applying a base to a diasteromeric mixture of compoundsrepresented by formula (Va) results in easy formation of compoundsrepresented by formula (Vb). The present invention was accomplishedbased on these findings.

[0027] The present invention is generally represented by the followingreaction schemes I and II:

[0028] [wherein R¹ represents a protective group for a nitrogen atom; R²represents a methanesulfonyl group or a p-toluenesulfonyl group; R³represents a hydrogen atom, an aralkyl group, or an alkyl group having 1to 6 carbon atoms; and X¹ represents a leaving group].

[0029] Accordingly, the present invention provides a process forpreparing a compound represented by formula (III) or (IIIa) or saltsthereof through reaction of a compound represented by formula (I) or(Ia) and a compound represented by formula (II) in the presence of abase.

[0030] The present invention also provides a process for preparing acompound represented by formula (V) (or (Va)) or salts thereof throughreaction of a compound represented by formula (III) (or (IIIa)) or asalt thereof and a compound represented by formula (IV) in the presenceof a base.

[0031] The present invention further provides a process for preparing acompound represented by formula (Vb) through reaction of a compoundrepresented by formula (Va) and a base.

[0032] The present invention still further provides a process forpreparing a compound represented by formula (IVa):

[0033] [wherein X² represents a halogen atom]; through halogenation of acompound represented by formula (VII) in an alkylnitrile solvent.

[0034] Of the compounds appearing in the above-described reactionschemes, some are novel compounds that have been newly found in thepresent invention. Accordingly, the present invention is also directedto such novel compounds which are useful as synthesis intermediates.

[0035] The present invention further provides compounds represented byformula (III):

[0036] [wherein R¹ and R³ have the same meanings as described above],and salts thereof.

[0037] The present invention further provides compounds represented byformula (IIIa):

[0038] [wherein R¹ and R³ have the same meanings as described above],and salts thereof.

[0039] The present invention still further provides compoundsrepresented by formula (Vc):

[0040] [wherein R^(1c) represents a tertiary butoxycarbonyl group andR^(3c) represents a hydrogen atom, an aralkyl group, or an alkyl grouphaving 1 to 6 carbon atoms(other than an ethyl group)], and saltsthereof.

[0041] The present invention yet further provides compounds representedby formula (Vd):

[0042] [wherein R^(1d) represents a benzyl group and R^(3d) represents ahydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbonatoms], and salts thereof.

[0043] Best Mode for Carrying Out the Invention

[0044] The present will next be described in detail. Firstly, thesubstituents of the compounds according to the present invention aredescribed.

[0045] R¹ represents a protective group for the nitrogen atom.Protective groups which are typically used may be employed for theprotective group. Examples include a tert-butoxycarbonyl group, abenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a benzylgroup, a formyl group, an acetyl group, and a triphenylmethyl group. Inthe present invention, a tert-butoxycarbonyl group or a benzyl group ispreferred.

[0046] R² represents a methanesulfonyl group or a p-toluenesulfonylgroup.

[0047] The alkyl group having 1 to 6 carbon atoms represented by R³ maybe linear, branched, or cyclic, and examples thereof include a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a tert-butyl group, a pentyl group, a hexylgroup, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, anda cyclohexyl group. The aralkyl group is a group formed of an alkylgroup having 1 to 6 carbon atoms and an aryl group, and examples thereofinclude a benzyl group and a naphthylmethyl group. The group R³ in thepresent invention is preferably an alkyl group having 1 to 6 carbonatoms, more preferably a methyl group or an ethyl group.

[0048] X¹ represents a leaving group. As the leaving group, any such agroup which is usually used may be employed, and examples include ahalogen atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxygroup. As used herein, examples of the halogen atom include a fluorineatom, a chlorine atom, a bromine atom, and an iodine atom. Of these, abromine atom is particularly preferred.

[0049] X² represents a halogen atom. Examples of the halogen atominclude a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom. Among others, a bromine atom is preferred.

[0050] The compounds represented by formula (I) or formula (Ia), thecompounds represented by formula (II), and the compounds represented byformula (VII) used in the present invention are easily available knowncompounds or compounds which can easily be produced according toliterature.

[0051] The compounds represented by formula (I) are known compounds, andoptically active(3R)-1-(tert-butoxylcarbonyl)-3-methanesulfonyloxypyrrolidine (seeJapanese Patent Application Laid-Open (kokai) No. 2-28180) and opticallyactive (3R)-1-(tert-butoxylcarbonyl)-3-p-toluenesulfonyloxypyrrolidine(see WO 9200295) represented by formula (Ia) are also known compounds.

[0052] Among the compounds represented by formula (II), methylp-hydroxyphenylacetate and ethyl p-hydroxyphenylacetate are knowncompounds. Other p-hydroxyphenylacetic acid alkyl esters can easily beproduced from the condensation use of the corresponding alcohol andeasily available p-hydroxyphenylacetic acid.

[0053] 7-Halomethyl-2-naphthalenecarbonitrile, which is an examplecompound of formula (IV), is also a known compound (Japanese PatentApplication Laid-Open (kokai) Nos. 5-208946 and 7-17937).

[0054] The production process of the present invention will next bedescribed in detail.

[0055] [Step A] Method for Preparing a Compound Represented by Formula(III) or Formula (IIIa) or Salts Thereof:

[0056] In order to obtain a compound represented by formula (III) orformula (IIIa) or salts thereof, a compound represented by formula (I)or formula (Ia) is reacted with a compound represented by formula (II)in the presence of a base and optionally an catalyst.

[0057] No particular limitation is imposed on the solvent used in thisstep so long as it provides no adverse effect on the reaction. Examplesof the solvent include organic solvents such as aprotic polar solvents,ethers, aromatic hydrocarbons, and alcohols; mixtures of the organicsolvents; and mixtures of the organic solvents and water.

[0058] Examples of the aprotic polar solvents includeN,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, andacetonitrile. Examples of the ethers include tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether, and triethyleneglycol dimethyl ether. Examples of the aromatic hydrocarbons includebenzene, toluene, and xylene. Examples of the alcohols include methanoland ethanol. Among the solvents, aprotic polar solvents or aromatichydrocarbons are preferably used, with N,N-dimethylformamide or toluenebeing more preferred.

[0059] No particular limitation is imposed on the base so long as itprovides no adverse effect on the reaction, and a weak or strong basemay be used. Examples of a strong base include an alkali metal hydridesuch as sodium hydride or lithium hydride; an alkaline earth metalhydride such as calcium hydride; an alkali metal alkoxide such as sodiummethoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodiumtert-butoxide, or potassium tert-butoxide; an alkali metal hydroxidesuch as sodium hydroxide or potassium hydroxide; and an alkali metalcarbonate such as sodium carbonate or potassium carbonate. Strong basesare preferred. Particularly, an alkali metal hydride is preferred, withsodium hydride being more preferred.

[0060] Examples of the catalyst which is used in the present inventioninclude phase-transfer catalysts and molecular sieves. Examples of thephase-transfer catalysts include oleophilic quaternary ammonium saltssuch as tetra(n-butyl)ammonium bromide, tetra(n-butyl)ammonium chloride,tetraethylammonium bromide, tetra(n-butyl)ammonium hydrogensulfide,triethylbenzylammonium bromide, or triethylbenzylammonium chloride; andcrown ethers such as 18-crown-6,15-crown-5. Phase-transfer catalysts arepreferred. Particularly, oleophilic quaternary ammonium salts arepreferred, with tetra(n-butyl)ammonium bromide being more preferred.Addition of the catalysts increases the yield of the compoundsrepresented by formula (III) or formula (IIIa) or salts thereof.

[0061] No particular limitation is imposed on the reaction temperatureso long as it is not greater than the boiling point of the solvent. Thereaction is typically performed within the temperature range from 0° C.to about the boiling point of the solvent used, preferably at 60°C.-110° C. The reaction time varies in accordance with the reactiontime, and the reaction is performed typically for 15 minutes to one day,preferably for 4 hours or less.

[0062] [Step B] Method for Preparing a Compound Represented by Formula(IV)

[0063] The compound represented by formula (IV) may be obtained througha known method, and is preferably obtained through halogenation of acompound represented by formula (VII) in an alkylnitrile solvent. Aradical initiator may be added during the halogenation.

[0064] No particular limitation is imposed on the alkylnitrile solventso long as it provides no adverse effect on the reaction, and C2-C7linear or branched alkylnitriles may be used. Examples of the C2-C7linear or branched alkylnitriles include acetonitrile, propionitrile,n-butyronitrile, isobutyronitrile, valeronitrile, hexanenitrile, andheptanenitrile. Of these, linear or branched alkylnitriles having 2 to 4carbon atoms such as acetonitrile, propionitrile, n-butyronitrile, orisobutyronitrile are preferred, with acetonitrile being more preferred.

[0065] No particular limitation is imposed on the radical initiator solong as it provides no adverse effect on the reaction, and examplesthereof include peroxides such as dibenzoyl peroxide or azo compoundssuch as azobisisobutyronitrile. Instead of adding a radical initiator,operations such as light irradiation or heating may be performed. Of avariety of radical initoators, azo compounds are preferred, with2,2′-azobisisobutyronitrile being particularly preferred.

[0066] The halogenation may be performed by adding a halogenating agent.No particular limitation is imposed on the halogenating agent so long asit provides no adverse effect on the reaction. Examples thereof includesulfuryl halides and N-halogenoimides. Of these, N-halogenoimides arepreferred, with N-bromosuccinimide being more preferred.

[0067] No particular limitation is imposed on the reaction temperatureso long as it is not higher than the boiling point of the solvent. Thereaction is typically performed at 40° C.-120° C., preferably at about80° C. The reaction time depends on the reaction temperature, and thereaction is typically performed for one hour to one day, preferably for1-4 hours.

[0068] [Step C] Method for Preparing a Compound Represented by Formula(V) or Formula (Va) or Salts Thereof

[0069] In order to obtain a compound represented by formula (V) orformula (Va) or a salt thereof, a compound represented by formula (III)or formula (IlIa) is reacted with a compound represented by formula (IV)in the presence of a base.

[0070] No particular limitation is imposed on the solvent in the step solong as it provides no adverse effect on the reaction. Examples of thesolvent include organic solvents such as aprotic polar solvents, ethers,esters, aromatic hydrocarbons, and alcohols; mixtures of the organicsolvents; and mixtures of the organic solvents and water.

[0071] Examples of the aprotic polar solvents includeN,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, andacetonitrile. Examples of the ethers include tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether, and triethyleneglycol dimethyl ether. Examples of the esters include methyl acetate,ethyl acetate, methyl propionate, and ethyl propionate. Examples of thearomatic hydrocarbons include benzene, toluene, and xylene. Examples ofthe alcohols include methanol and ethanol. The mixtures of the organicsolvents are preferably used. Of these, mixtures of an aprotic polarsolvent and an aromatic hydrocarbon are preferred, with a mixturecomprising N,N-dimethylformamide and toluene being more preferred.

[0072] No particular limitation is imposed on the base so long as itprovides no adverse effect on the reaction, and a weak or strong basemay be used. Examples of a strong base include an alkali metal hydridesuch as sodium hydride, or lithium hydride; an alkaline earth metalhydride such as calcium hydride; an alkali metal alkoxide such as sodiummethoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodiumtert-butoxide, or potassium tert-butoxide; an alkali metal hydroxidesuch as sodium hydroxide or potassium hydroxide; and an alkali metalcarbonate such as sodium carbonate or potassium carbonate. Strong basesare preferred. Particularly, an alkali metal hydride is preferred, withsodium hydride being more preferred.

[0073] No particular limitation is imposed on the reaction temperatureso long as it is not higher than the boiling point of the solvent,however, the reaction is preferably performed at comparatively lowtemperature in order to suppress a side reaction. The reaction isperformed typically within the temperature range from −10° C. to roomtemperature, preferably at 60° C.-110° C. The reaction time varies inaccordance with the reaction temperature, and the reaction is performedtypically for one hour to one day, preferably for 3-12 hours.

[0074] The thus-obtained 2-phenyl-3-naphthylpropionic acid derivatives,which are compounds represented by formula (V) or formula (Va), areimportant intermediates of aromatic amidine derivatives described inJapanese Patent Application Laid-Open (kokai) No. 5-208946.

[0075] Steps A and C; Steps B and C; or Steps A, B, and C may beperformed continuously. Briefly, a compound represented by formula (III)or formula (IIIa) or a salt thereof that is obtained through Step A anda compound represented by formula (IV) or a salt thereof that isobtained through Step B may be used in the subsequent Step C withoutisolating the compounds at respective steps.

[0076] An example of the sequential steps will next be described.Firstly, in Step A, a compound represented by formula (III) or formula(IIIa) or a salt thereof is obtained through reaction in an aromatichydrocarbon solvent by use of a phase-transfer catalyst in the presenceof a strong base. Then, in Step B, a compound represented by formula(IV) obtained through reaction in an alkylnitrile is extracted with anaromatic hydrocarbon. Subsequently, a compound represented by formula(III) or formula (IIIa) or a salt thereof and a compound represented byformula (IV) are reacted, without isolating these compounds, in asolvent mixture comprising an aromatic hydrocarbon solvent containing anaprotic polar solvent in the presence of a strong base, to therebyobtain a compound represented by formula (V) or formula (Va) or a saltthereof.

[0077] The sequential steps requiring no operation such as isolation ispreferred as an industrial process. In particular, since isolatedcrystals of 7-bromomethyl-2-naphthalenecarbonitrile exhibit skinirritation, Step B and Step C are preferably performed sequentially.

[0078] [Step] Method for Preparing an Optically Active CompoundRepresented by Formula (Vb)

[0079] In order to obtain a compound represented by formula (Vb) from acompound represented by formula (Va), a compound represented by formula(Va) may be reacted with a base.

[0080] Briefly, a compound represented by (Va) that is a mixture of anR-diastereomer and an S-diastereomer is reacted with a base, to therebyobtain a compound represented by formula (Vb), which is anS-diastereomer.

[0081] Specifically, the R-diastereomer is dissolved in a solvent whichis appropriate for inducing crystallization of the S-diastereomer and isreacted in the dissolved state with a base, to thereby effect conversionfrom the R-diastereomer to the S-diastereomer. The target S-diastereomeris then crystallized through the difference in solubility between theR-diastereomer and the S-diastereomer.

[0082] In this case, no particular limitation is imposed on the solventso long as it provides no adverse effect on the reaction, and there maybe used a solvent which allows crystallization of compounds representedby formula (Vb). Specifically, protic solvents including water andalcohols may be used. These solvents may be used singly or incombination. The protic solvents may be blended with aprotic polarsolvents, ethers, hydrocarbons, or mixtures thereof to thereby serve asa solvent.

[0083] Examples of the alcohols include methanol and ethanol. Examplesof the aprotic polar solvents include N,N-dimethylformamide, dimethylsulfoxide, and acetonitrile. Examples of the ethers include isopropylether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycoldimethyl ether, and triethylene glycol dimethyl ether. Examples of thehydrocarbons include benzene, toluene, xylene, n-hexane, and n-pentane.

[0084] No particular limitation is imposed on the base so long as itprovides no adverse effect on the reaction. Examples of the strong baseinclude alkali metal alkoxides such as sodium methoxide, lithiummethoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide, orpotassium tert-butoxide; alkali metal amides such as sodium amides; andalkali metal hydroxides such as sodium hydroxide or potassium hydroxide,and alkali metal carbonates such as sodium carbonate or potassiumcarbonate. Strong bases are preferably used. Of these, alkali metalalkoxides are preferred, with sodium ethoxide being more preferred.

[0085] The amount of the base is not limited so long as it provides noadverse effect on the reaction, and it is preferably 10-30%mol-equivalent based on the compound represented by formula (Va).

[0086] No particular limitation is imposed on the reaction temperatureso long as it is not greater than the boiling point of the solvent. Thereaction is performed typically in a temperature range from −10° C. toroom temperature, preferably in a range from 10° C. to room temperature.The reaction time varies in accordance with the reaction temperature,and the reaction is performed typically for 30 minutes to several days,preferably for 20 hours or less.

[0087] The thus-obtained optically active2-phenyl-3-naphthalenepropionic acid derivatives, which are compoundsrepresented by formula (Vb), are important intermediates of aromaticamidine derivatives described in the cited reference.

[0088] The aromatic amidine derivatives or salts thereof may be preparedfrom compounds represented by formula (V), (Va), or (Vb) through amethod described in Japanese Patent Application Laid-Open (kokai) No.5-208946.

EXAMPLES

[0089] The present invention will next be described in detail by way ofExamples, which should not be construed as limiting the inventionthereto.

Example 1 Method for Preparing(3R)-1-benzyl-3-methanesulufonyloxypyrrolidine

[0090] (3R)-1-Benzyl-3-pyrrodinol (10.0 g, 56 mmol) and triethylamine(6.6 g, 65 mmol) were dissolved in toluene (100 ml), and the resultantsolution was cooled to 5° C. Into this solution, methanesulfonylchloride (7.1 g, 62 mmol) was added dropwise over 10 minutes at 5° C.After stirring the mixture for 30 minutes, toluene (100 ml) was addedthereto, then the resultant solution was heated to room temperature andstirred for 1.5 hours. The reaction mixture was washed with saturatedsodium bicarbonate water (200 ml), then with water (100 ml) twice. Afterconcentration of the resultant organic layer under reduced pressure, theresidue was subjected to column chromatography to yield 9.8 g of thetitle composition (yield: 68%).

[0091] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 2.19 (1 H, m),2.30 (1 H, m), 2.49 (1 H, m), 2.76-2.89 (3 H, m) 2.99 (3 H, s), 3.64 (2H, dd, J=12.9, 12.9 Hz) 5.20 (1 H, m), 7.25-7.35 (5 H, m)

[0092] Elementary Analysis C₁₂H₁₇NSO₃:

[0093] Calculated: C, 56.45; H, 6.71; N, 5.49 Found: C, 55.70; H, 6.33;N, 5.48

[0094] FABMS(m/z): 256(M⁺+1) Infrared Absorption Absorption Spectrumνmax (KBr) cm⁻¹: 3028, 2944, 2804, 1496, 1454, 1356, 1170, 1146, 966

[0095] Angle of Rotation [α]²²D=+14.0° (c=1.0, MeOH)

Example 2 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0096] p-Hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) wasdissolved in dimethylformamide (500 ml). A solution of 60% sodiumhydride (8.8 g, 0.22 mol) was added to the mixture at room temperature.Forty minutes later,(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxypyrrolidine (53.1 g,0.2 mol) was added thereto and heated for 15 minutes at an internaltemperature of 110° C. The resultant mixture was cooled to roomtemperature, and concentrated by evaporating the solvent under reducedpressure. Acetic acid ethyl ester (500 ml) was added to the residue soas to dissolve the residue. The resultant solution was washed 4 timeswith aqueous 10% potassium hydroxide solution (100 ml). The organiclayer was concentrated under reduced pressure, and the residue wassubjected to silica gel column chromatography to yield 39.8 g of thetitle compound (yield: 57%).

[0097] Melting point: 39 to 40° C.

[0098] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.25 (3 H, t,J=6.9 Hz), 1.47(9 H, s), 2.08-2.17 (2 H, m), 3.46-3.63 (4 H, m) 3.54 (2H, s), 4.14 (2 H, q, J=6.9 Hz), 4.86 (1 H, m), 6.83 (2 H, d, J=8.3 H z)7.24 (2 H, d, J=8.3 Hz)

[0099] Elementary Analysis C₁₉H₂₆NO₅:

[0100] Calculated: C, 65.31; H, 7.79; N, 4.01 Found: C, 65.20; H, 7.59;N, 3.76

[0101] MS (m/Z): 349(M⁺) Infrared Absorption Absorption Spectrum νmax(KBr) cm⁻¹: 2984, 1736, 1694, 1514, 1482, 1410, 1370, 1168, 1116

[0102] Angle of Rotation [α]²²D=22.2° (c=1.0, CHCl₃)

Example 3 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0103] p-Hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) wasdissolved in dimethylformamide (500 ml), and then 60% sodium hydride(8.8 g, 0.22 mol) was added to the mixture at room temperature. Fortyminutes later,(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxypyrrolidine (53.1 g,0.2 mol) was added thereto and the mixture was heated for 15 minutes atan internal temperature of 110° C. The resultant mixture was cooled toroom temperature, and then was concentrated to remove the solvent underreduced pressure. Acetic acid ethyl ester (500 ml) was added to dissolvethe residue, and the resultant solution was washed 4 times with 10%potassium hydroxide aqueous solution (100 ml). Analysis byreversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 43.7 g of the titlecompound having a purity of 79% was obtained (62% yield).

Example 4 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0104] Procedures of Example 3 were repeated in dimethyl sulfoxide (25ml) except that p-hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol),(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (2.5 g, 10mmol), and 60% sodium hydride (440 mg, 10 mmol) were used. Analysis byreversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 1.8 g of the title compoundwas obtained (52% yield).

Example 5 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0105] Procedures of Example 3 were repeated in dimethylformamide (25ml) except that p-hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol),(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (2.5 g, 10mmol), and sodium ethoxide (0.7 g, 10 mmol) were used. Analysis byreversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 1.7 g of the title compoundwas obtained (50% yield).

Example 6 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0106] Procedures of Example 3 were repeated in dimethylformamide (25ml) except that p-hydroxyphenylacetic acid ethyl ester (2.0 g, 11 mmol),(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (2.5 g, 10mmol), and potassium tert-butoxide (1.2 g, 11 mmol) were used. Analysisby reversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 2.0 g of the title compoundwas obtained (58% yield).

Example 7 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0107] Procedures of Example 3 were repeated in dimethylformamide (68ml) except that p-hydroxyphenylacetic acid ethyl ester (4.0 g, 22 mmol),(3R)-1-(tert-butoxycarbonyl)-3-p-toluenesulfonyloxy pyrrolidine (6.8 g,20 mmol), and 60% sodium hydride (880 mg, 22 mmol) were used. Analysisby reversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 4.4 g of the title compoundwas obtained (64% yield).

Example 8 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0108] p-Hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol) wasdissolved in ethanol (25 ml), and then sodium ethoxide (0.7 g, 10 mmol)was added to the mixture at room temperature. Forty minutes later,(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (2.5 g, 10mmol) was added thereto and the mixture was subjected to heating andrefluxing for 3 hours. The resultant mixture was cooled to roomtemperature, and then was concentrated to remove the solvent underreduced pressure. Acetic acid ethyl ester (30 ml) was added to dissolvethe residue, and the resultant solution was washed 4 times with 10%potassium hydroxide aqueous solution (20 ml). Analysis by reversed-phasechromatography by use of the obtained product from Example 2 as astandard sample revealed that 0.9 g of the title compound was obtained(25% yield).

Example 9 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0109] Procedures of Example 8 were repeated in acetonitrile (26 ml)except that p-hydroxyphenylacetic acid ethyl ester (2.0 g, 11 mmol),(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (2.5 g, 10mmol), and 60% sodium hydride (440 mg, 11 mmol) were used. Analysis byreversed-phase chromatography by use of the obtained product fromExample 2 as a standard sample revealed that 2.2 g of the title compoundwas obtained (64% yield).

Example 10 Method for Preparing2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester

[0110] p-Hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) wasdissolved in toluene (530 ml), and then 60% sodium hydride (8.8 g, 0.22mol) was added to the mixture at room temperature. After heating themixture at an internal temperature of 45° C. for one hour,(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (53.1 g,0.2 mol) and tetranormalbutylammonium bromide (19.3 g, 60 mmol) wereadded thereto. The resultant mixture was heated at an internaltemperature of 80° C. for 3 hours, and then was cooled to roomtemperature. The mixture was washed three times with 10% potassiumhydroxide aqueous solution (106 ml). Analysis by reversed-phasechromatography by use of the obtained product from Example 2 as astandard sample revealed that 49.0 g of the title compound having apurity of 79% was obtained (70% yield).

Example 11 Method for Preparing 7-bromomethyl-2-naphthalene carbonitrile

[0111] 2,2′-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile(100 ml) were added to 7-methyl-2-naphthalene carbonitrile (10.0 g, 60mmol) at room temperature. N-bromosuccinimide (10.6 g, 60 mmol) wasadded thereto, and the mixture was subjected to heating and refluxingfor 2 hours. The resultant mixture was cooled to room temperature. Water(100 ml) and toluene (100 ml) were added to the mixture for extraction.The resultant organic layer was washed twice with water (100 ml). Afterconcentration of the organic layer under reduced pressure, the residuewas subjected to silica-gel-column chromatography to yield 11.4 g of thetitle compound (78% yield). The data measured by instruments agreed withthe data described in J. Med. Chem., 1991, 3105.

Example 12 Method for Preparing 7-bromomethyl-2-naphthalene carbonitrile

[0112] 2,2′-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile(100 ml) were added to 7-methyl-2-naphthalene carbonitrile (10.0 g, 60mmol) at room temperature. N-bromosuccinimide (10.6 g, 60 mmol) wasadded thereto, and the mixture was subjected to heating and refluxingfor 2 hours. The resultant mixture was cooled to room temperature. Water(100 ml) and toluene (100 ml) were added to the mixture for extraction.The resultant organic layer was washed twice with water (100 ml). Afterconcentration of a part of the organic layer under reduced pressure,analysis of the residue by reversed-phase chromatography by use of theobtained product from Example 11 as a standard sample revealed that 12.1g of the title compound was obtained (82% yield).

Example 13 Method for Preparing 7-bromomethyl-2-naphthalene carbonitrile

[0113] 2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and propionitrile(50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was addedthereto, and the mixture was heated at an internal temperature of 80° C.for 4 hours. After that, the experiment was conducted in the same way asExample 12. Analysis by reversed-phase chromatography by use of theobtained product from Example 11 as a standard sample revealed that 1.9g of the title compound was obtained (26% yield).

Example 14 Method for Preparing 7-bromomethyl-2-naphthalene carbonitrile

[0114] 2,2′-azobisisobutyronitrile (491 mg, 3 mmol) andnormalbutyronitrile (50 ml) were added to 7-methyl-2-naphthalenecarbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide(5.3 g, 30 mmol) was added thereto, and the mixture was heated at aninternal temperature of 80° C. for 2 hours. After that, the experimentwas conducted in the same way as Example 12. Analysis by reversed-phasechromatography by use of the obtained product from Example 11 as astandard sample revealed that 5.4 g of the title compound was obtained(74% yield).

Example 15 Method for Preparing 7-bromomethyl-2-naphthalene carbonitrile

[0115] 2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and isobutyronitrile(50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was addedthereto, and the mixture was heated at an internal temperature of 80° C.for 2 hours. After that, the experiment was conducted in the same way asExample 12. Analysis by reversed-phase chromatography by use of theobtained product from Example 11 as a standard sample revealed that 4.3g of the title compound was obtained (58% yield).

Example 16 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0116]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.8 g, 5 mmol) obtained from Example 2 and7-bromomethyl-2-naphthalene carbonitrile (1.5 g, 6 mmol) were dissolvedin dimethylformamide (15 ml), and the mixture was cooled to 0° C. Then,60% sodium hydride (0.2 g, 5.5 mmol) was added thereto, and the mixturewas stirred at the same temperature for 2.5 hours. The resultant mixturewas diluted with acetic acid ethyl ester (30 ml), and was washed threetimes with water (10 ml). After concentration of the resultant organiclayer under reduced pressure, the residue was subjected tosilica-gel-column chromatography to yield 2.37 g of the title compound(89% yield). The data measured by instruments agreed with the data ofReference Example 35 described in Japanese Patent Application Laid-Open(kokai) No. 5-208946.

Example 17 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0117]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (40.0 g, 0.12 mol, purity: 79%) obtained from Example 3 and7-bromomethyl-2-naphthalene carbonitrile (33.8 g, 0.14 mol) weredissolved in dimethylformamide (340 ml), and the mixture was cooled to0° C. Then, 60% sodium hydride (5.0 g, 0.13 mol) was added thereto, andthe mixture was stirred at the same temperature for 3 hours. Theresultant mixture was diluted with acetic acid ethyl ester (680 ml), andwas washed three times with water (170 ml). Analysis by reversed-phasechromatography by use of the obtained product from Example 16 as astandard sample revealed that 54.1 g of the title compound having apurity of 66% was obtained (92% yield).

Example 18 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0118]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (40.0 g, 0.12 mol, purity: 79%) obtained from Example 10 and7-bromomethyl-2-naphthalene carbonitrile (33.8 g, 0.14 mol) weredissolved in dimethylformamide (400 ml), and the mixture was cooled to0° C. Then, 60% sodium hydride (5.0 g, 0.13 mol) was added thereto, andthe mixture was stirred at the same temperature for 3 hours. Theresultant mixture was diluted with acetic acid ethyl ester (800 ml), andwas washed three times with water (200 ml). Analysis by reversed-phasechromatography by use of the obtained product from Example 16 as astandard sample revealed that 53.5 g of the title compound having apurity of 67% was obtained (91% yield).

Example 19 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0119] Procedures of Example 17 were repeated in dimethylformamidehaving 0.2% water (10 ml) except that 2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (1.0 g, 2.8 mmol), 7-bromomethyl-2-naphthalene carbonitrile (0.7g, 2.8 mmol), and 60% sodium hydride (0.1 g, 3.1 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 1.3 g of the titlecompound was obtained (90% yield).

Example 20 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0120] Procedures of Example 17 were repeated in a mixture consisting ofdimethylformamide (7.5 ml) and toluene (7.5 ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.8 g, 5 mmol), 7-bromomethyl-2-naphthalene carbonitrile(1.5 g, 6 mmol), and 60% sodium hydride (0.2 g, 5.5 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 2.7 g of the titlecompound was obtained (92% yield).

Example 21 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0121] Procedures of Example 17 were repeated in a mixture consisting oftriethylene glycol dimethyl ether (9 ml) and toluene (9 ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.8 g, 5 mmol), 7-bromomethyl-2-naphthalene carbonitrile(1.5 g, 6 mmol), and 60% sodium hydride (0.2 g, 5.5 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 1.8 g of the titlecompound was obtained (71% yield).

Example 22 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0122] Procedures of Example 17 were repeated in triethylene glycoldimethyl ether (46 ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (3.5 g, 10 mmol), 7-bromomethyl-2-naphthalene carbonitrile(3.0 g, 12 mmol), and 60% sodium hydride (0.4g, 11 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 4.4 g of the titlecompound was obtained (86% yield).

Example 23 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0123] Procedures of Example 17 were repeated in dimethylformamide (15ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.7 g, 5 mmol), 7-bromomethyl-2-naphthalene carbonitrile(1.5 g, 6 mmol), and sodium ethoxide (0.4 g, 5.5 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 1.6 g of the titlecompound was obtained (65% yield).

Example 24 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0124] Procedures of Example 17 were repeated in dimethylformamide (15ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.7 g, 5 mmol), 7-bromomethyl-2-naphthalene carbonitrile(1.5 g. 6 mmol), and potassium tert-butoxide (0.6 g, 5.5 mmol) wereused. Analysis by reversed-phase chromatography by use of the obtainedproduct from Example 16 as a standard sample revealed that 1.0 g of thetitle compound was obtained (38% yield).

Example 25 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0125] Procedures of Example 17 were repeated in dimethylformamide (10ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.0 g, 2.8 mmol), 7-chloromethyl-2-naphthalene carbonitrile(0.6 g, 2.8 mmol), and sodium hydride (0.1 g, 3.1 mmol) were used.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 16 as a standard sample revealed that 0.9 g of the titlecompound was obtained (61% yield).

Example 26 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0126] Procedures of Example 17 were repeated in dimethylformamide (10ml) except that2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (1.0 g, 2.8 mmol),7-p-toluenesulfonyloxymethyl-2-naphthalene carbonitrile (0.9 g, 2.8mmol), and 60% sodium hydride (0.1 g, 3.1 mmol) were used. Analysis byreversed-phase chromatography by use of the obtained product fromExample 16 as a standard sample revealed that 0.9 g of the titlecompound was obtained (64% yield).

Example 27 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0127] p-Hydroxyphenylacetic acid ethyl ester (1.4 g, 7.9 mmol) wasdissolved in toluene (20 ml), and then 60% sodium hydride (310 mg, 7.9mmol) was added to the mixture at room temperature. After heating themixture at an internal temperature of 45° C. for one hour,(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (1.9 g,7.1 mmol) and tetranormalbutylammonium bromide (690 mg, 2.4 mmol) wereadded thereto. The resultant mixture was heated at an internaltemperature of 80° C. for 3 hours, and then was cooled to roomtemperature. The mixture was washed three times with 10% potassiumhydroxide aqueous solution (4 ml). Analysis by reversed-phasechromatography by use of the obtained product from Example 2 as astandard sample revealed that 1.7 g of2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester was obtained (70% yield).

[0128] Without concentration of the resultant organic layer,7-bromomethyl-2-naphtalenecarbonitrile (1.5 g, 6 mmol) anddimethylformamide (20 ml) were added to the organic layer, and themixture was cooled to 0° C. Then, 60% sodium hydride (220 mg, 5.5 mmol)was added thereto, and the resultant mixture was stirred at the sametemperature for 10 hours. The reaction mixture was washed three timeswith water (20 ml), and analysis by reversed-phase chromatography by useof the obtained product from Example 16 as a standard sample revealedthat 2.4 g of the title compound was obtained (92% yield). The overallyield over the two steps was 64%.

Example 28 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0129] Procedures of Example 27 were repeated except thatp-hydroxyphenylacetic acid ethyl ester (1.4 g, 7.9 mmol), toluene (20ml), 60% sodium hydride (310 mg, 7.9 mmol),(3R)-1-(tert-butoxycarbonyl)-3-methanesulfonyloxy pyrrolidine (1.9 g,7.1 mmol) and tetranormalbutylammonium bromide (690 mg, 2.4 mmol) wereused. The resultant organic layer was analyzed by reversed-phasechromatography by use of the obtained product from Example 2 as astandard sample revealed that 1.7 g of2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester was obtained (70% yield).

[0130] Without concentration of the resultant organic layer,7-bromomethyl-2-naphtalenecarbonitrile (1.5 g, 6 mmol) anddimethylformamide (20 ml), and then 60% sodium hydride (220 mg, 5.5mmol) were added thereto, and the resultant mixture was stirred at roomtemperature for 8 hours. The reaction mixture was washed three timeswith water (20 ml), and analysis by reversed-phase chromatography by useof the obtained product from Example 16 as a standard sample revealedthat 2.3 g of the title compound was obtained (88% yield). The overallyield over the two steps was 61%.

Example 29 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0131] 2,2′-azobisisobutyronitrile (624 mg, 3.8 mmol) and acetonitrile(65 ml) were added to 7-methyl-2-naphthalene carbonitrile (6.3 g, 38mmol) at room temperature. N-bromosuccinimide (6.8 g, 38 mmol) was addedthereto, and the mixture was subjected to heating and refluxing for 2hours. The resultant mixture was cooled to room temperature. Water (65ml) and toluene (65 ml) were added to the mixture, and the mixture wassubjected to extraction. The resultant organic layer was washed twicewith water (65 ml). Analysis by reversed-phase chromatography by use ofthe obtained product from Example 11 as a standard sample revealed that7.4 g of 7-bromomethyl-2-naphthalene carbonitrile was obtained (80%yield).

[0132] Without concentration of this organic layer,2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidethyl ester (8.7 g, 25 mmol, purity: 79%) obtained from Example 10, anddimethylformamide (81 ml) were added thereto, and the resultant mixturewas cooled to 0° C. Then, 60% sodium hydride (1.1 g, 27.5 mmol) wasadded thereto, and the resultant mixture was stirred at the sametemperature for 5 hours. The resultant solution was diluted with toluene(40 ml) and washed three times with water (80 ml). The resultant organiclayer was concentrated under reduced pressure, and the residue (19.3 g)was analyzed by reversed-phase chromatography by use of the obtainedproduct from Example 16 as a standard sample revealed that 11.7 g of thetitle compound was obtained (91% yield).

Example 30 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0133]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidmethyl ester (1.7 g, 5 mmol), and 7-bromomethyl-2-naphthalenecarbonitrile (1.4 g, 5.5 mmol) were dissolved in dimethylformamide (15ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (0.2g, 5.5 mmol) was added thereto, and the resultant mixture was stirred atthe same temperature for 3 hours. The resultant mixture was diluted withacetic acid ethyl ester (30 ml), and was washed three times with water(10 ml). The resultant organic layer was concentrated under reducedpressure, and the residue was subjected to silica-gel-columnchromatography to yield 2.3 g of the title compound (93% yield).

[0134] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.47 (9 H, s),2.14 (2 H, m), 3.19 (1 H, d d, J=6.9, 13.9 Hz), 3.55 (5 H, m), 3.60 (3H, s), 3.90 (1 H, br), 4.86 (1 H, m) 6.83 (2 H, d, J=8.6 Hz), 7.23 (2 H,d, J=8.3 Hz), 7.41 (1 H, dd, J=1.5, 8.3 Hz), 7.56 (1 H, dd, J=1.5, 8.3Hz), 7.61 (1 H, s), 7.78 (1H, d, J=8.3 Hz), 7.85 (1 H, d, J=8.3 Hz),8.13 (1 H, s)

Example 31 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid isopropyl ester

[0135]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidisopropyl ester (1.8 g, 5 mmol), and 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) were dissolved in dimethylformamide (15ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (0.2g, 5.5 mmol) was added thereto, and the resultant mixture was stirred atthe same temperature for 5 hours. The resultant mixture was diluted withacetic acid ethyl ester (30 ml), and was washed three times with water(10 ml). The resultant organic layer was concentrated under reducedpressure, and the residue was subjected to silica-gel-columnchromatography to yield 2.4 g of the title compound (92% yield).

[0136] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.05 (3 H, d,J=6.3 Hz), 1.08 (3 H, d, J=5.6 Hz) 1.47 (9 H, s) 2.14 (2 H, m), 3.17 (1H, dd, J=6.6, 13.7 Hz), 3.55 (5 H, m), 3.85 (1 H, br), 4.86 (1 H, m),4.90 (1 H, m), 6.83 (2 H, d, J=8.6 Hz), 7.23 (2 H, br), 7.42 (1 H, d,J=8.3 Hz), 7.55 (1 H, d, J=1.6, 8.6 Hz), 7.62 (1 H, s), 7.79 (1 H, d,J=8.6 Hz), 7.84 (1 H, d, J=8.6 Hz), 8.13 (1 H, s)

Example 32 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid tert-butyl ester

[0137]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidtert-butyl ester (1.9 g, 5 mmol), and 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) were dissolved in dimethylformamide (15ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (0.2g, 5.5 mmol) was added thereto, and the resultant mixture was stirred atthe same temperature for 4 hours, followed by stirring at roomtemperature for four hours. The resultant mixture was diluted withacetic acid ethyl ester (30 ml), and was washed three times with water(10 ml). The resultant organic layer was concentrated under reducedpressure, and the residue was subjected to silica-gel-columnchromatography to yield 2.1 g of the title compound (79% yield).

[0138] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.30 (9 H, s),1.47 (9 H, s) 2.13 (2 H, m), 3.13 (1 H, dd, J=6.6, 13.9 Hz), 3.52 (5 H,m), 3.79 (1 H, br), 4.87 (1 H, m), 6.83 (2 H, d, J=8.6 Hz), 7.21 (2 H,d, J=8.3 Hz), 7.43 (1 H, d, J=7.6 Hz), 7.55 (1 H, d, J=7.6 Hz), 7.62 (1H, s), 7.77 (1 H, d, J=8.6 Hz), 7.86 (1 H, d, J=8.6 Hz), 8.13 (1 H, s)

Example 33 Method for Preparing2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid benzyl ester

[0139]2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acidbenzyl ester (2.1 g, 5 mmol), and 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) were dissolved in dimethylformamide (15ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (0.2g, 5.5 mmol) was added thereto, and the resultant mixture was stirred atthe same temperature for 3 hours. The resultant mixture was diluted withacetic acid ethyl ester (30 ml), and was washed three times with water(10 ml). The resultant organic layer was concentrated under reducedpressure, and the residue was subjected to silica-gel-columnchromatography to yield 2.6 g of the title compound (90% yield).

[0140] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.47 (9 H, s),2.11 (2 H, m), 3.17 (1 H, dd), 3.51 (5 H, m), 3.93 (1 H, br), 4.83 (1 H,m), 4.92 (1 H, d, J=13.2 Hz), 5.10 (H, d, J=9.9 Hz), 6.83 (2 H, d, J=8.6Hz), 7.05-8.30 (7 H, m), 7.39 (1 H, d, J=8.2 Hz), 7.52 (1 H, d, J=9.9Hz) 7.55 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.83 (1 H, d, J=8.6 Hz) 7.99(1 H, s),

Example 34 Method for Preparing2-[4-[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethyl ester

[0141] p-Hydroxyphenylacetic acid ethyl ester (9.1 g, 49.5 mmol) wasdissolved in dimethylformamide (120 ml), and then 60% sodium hydride(2.0 g, 49.5 mmol) was added to the mixture at room temperature. After40 minutes, (3R)-1-benzyl-3-methanesulfonyloxy pyrrolidine (11.5 g, 45mmol) was added thereto, and the resultant mixture was immediatelyheated in the oil bath maintained at 135° C. After being heated at theinternal temperature of 110° C. for 15 minutes, the mixture was cooledto room temperature. The mixture was then concentrated to remove thesolvent under reduced pressure, and acetic acid ethyl ester (120 ml) wasadded to dissolve the residue. The resultant mixture was washed threetimes with 10% potassium hydroxide aqueous solution (24 ml). Theresultant organic layer was concentrated under reduced pressure, and theresidue was subjected to silica-gel-column chromatography to yield 10.9g of the title compound (71% yield).

[0142] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.24 (3 H, t,J=6.9 Hz) 1.98 (1 H, m), 2.29 (1 H, m), 2.60 (1 H, m), 2.74 (2 H, m),2.98 (1 H, dd, 6.3, 6.3 Hz), 3.52 (2 H, s), 3.67 (2 H, dd, 12.9, 12.9Hz), 4.13 (2 H, q, J=6.9 Hz), 4.80 (1 H, m), 6.78 (2 H, d, J=8.6 Hz),7.15 (2 H, d, J=8.9 Hz), 7.24-7.35 (5 H, m)

[0143] Elementary Analysis C₂₁H₂₅NO₃:

[0144] Calculated: C, 74.31; H, 7.42; N, 4.13 Found: C, 73.82; H, 7.36;N, 4.01

[0145] FABMS (m/Z): 340(M³⁰+1) Infrared Absorption Spectrum νmax (KBr)cm⁻¹: 2984, 2800, 1732, 1614, 1512, 1296, 1244, 1148, 1028

[0146] Angle of Rotation [α]²⁴D=+7.8°(c=1.0, CHCl₃)

Example 35 Method for Preparing2-[4-[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethyl ester

[0147] p-Hydroxyphenylacetic acid ethyl ester (9.9 g, 55 mmol) wasdissolved in dimethylformamide (120 ml), and then 60% sodium hydride(2.2 g, 55 mmol) was added to the mixture at room temperature. After 40minutes, (3R)-1-benzyl-3-methanesulfonyloxy pyrrolidine (12.8 g, 50mmol) was added thereto, and the resultant mixture was immediatelyheated in the oil bath maintained at 135° C. After being heated at theinternal temperature of 110° C. for 15 minutes, the mixture was cooledto room temperature. The mixture was then concentrated to remove thesolvent under reduced pressure, and acetic acid ethyl ester (120 ml) wasadded to dissolve the residue. The resultant mixture was washed threetimes with 10% potassium hydroxide aqueous solution (24 ml). Theresultant organic layer was concentrated under reduced pressure, andanalysis of the residue by reversed-phase chromatography by use of theobtained product from Example 34 as a standard sample revealed that 12.2g of the title compound was obtained (72% yield, purity: 82%).

Example 36 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0148] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (1.0 g, 3 mmol) obtained from Example 34 and7-bromomethyl-2-naphthalene carbonitrile (0.9 g, 3.6 mmol) weredissolved in dimethylformamide (10 ml), and the mixture was cooled to 0°C. Then, 60% sodium hydride (0.1 g, 3.3 mmol) was added thereto and themixture was stirred at the same temperature for 1.5 hours. The resultantmixture was diluted with acetic acid ethyl ester (30 ml), and was washedthree times with water (10 ml). After concentration of the resultantorganic layer under reduced pressure, the residue was subjected tosilica-gel-column chromatography to yield 0.3 g of the title compound(20% yield).

[0149] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.10 (3 H, t,J=6.9 Hz), 1.97 (H, m), 2.28 (1 H, m), 2.60 (1 H, m), 2.74 (2 H, m),2.97 (1 H, m), 3.16 (1 H, dd, J=6.9, 13.5 Hz), 3.54 (1 H, dd, J=8.9,13.5 Hz), 3.67 (2 H, dd, J=12.9, 12.9 Hz), 3.85 (H, dd, J=6.9, 8.6 Hz),3.99-4.13 (2 H, m), 4.79 (1 H, m), 6.76 (2 H, d, J=8.6 Hz), 7.20 (2 H,d, J=8.6 Hz), 7.23-7.34 (5 H, m), 7.41 (1 H, d, J=8.3 Hz), 7.54 (1 H,dd, J=8.6, 8.6 Hz), 7.60 (1 H, s), 7.76 (1 H, d, J=8.6 Hz), 7.85 (1 H,d, J=8.6 Hz), 8.1 (1 H, s)

[0150] Angle of Rotation [α]²²D=+3.9°(c=1.0, CHCl₃)

Example 37 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0151] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), andthe mixture was cooled to −10° C. Then, 60% sodium hydride (60 mg, 1.5mmol) was added thereto and the mixture was stirred at the sametemperature for 0.5 hours. After that, 7-bromomethyl-2-naphthalenecarbonitrile (370 mg, 1.5 mmol) was gradually added thereto, theresultant mixture was stirred at the same temperature for 4 hours. Theresultant mixture was diluted with acetic acid ethyl ester (15 ml), andwas washed three times with water (5 ml). After concentration of theresultant organic layer under reduced pressure, analysis byreversed-phase chromatography by use of the obtained product fromExample 36 as a standard sample revealed that 480 mg of the titlecompound was obtained (64% yield).

Example 38 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0152] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalene carbonitrile(440 mg, 1.8 mmol) were dissolved in dimethyoxyethane (5 ml), and themixture was cooled to 0° C. Then, 60% sodium hydride (66 mg, 1.65 mmol)was added thereto and the mixture was stirred at the same temperaturefor 5 hours. After that, procedures of Example 37 were repeated.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 36 as a standard sample revealed that 158 mg of the titlecompound was obtained (21% yield).

Example 39 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0153] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalene carbonitrile(440 mg, 1.8 mmol) were dissolved in diethylene glycol dimethyl ether (5ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (66mg, 1.65 mmol) was added thereto and the mixture was stirred at the sametemperature for 5 hours. After that, procedures of Example 37 wererepeated. Analysis by reversed-phase chromatography by use of theobtained product from Example 36 as a standard sample revealed that 555mg of the title compound was obtained (73% yield).

Example 40 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0154] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalene carbonitrile(440 mg, 1.8 mmol) were dissolved in triethylene glycol dimethyl ether(5 ml), and the mixture was cooled to 0° C. Then, 60% sodium hydride (66mg, 1.65 mmol) was added thereto and the mixture was stirred at the sametemperature for 6 hours. After that, procedures of Example 37 wererepeated. Analysis by reversed-phase chromatography by use of theobtained product from Example 36 as a standard sample revealed that 647mg of the title compound was obtained (85% yield).

Example 41 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0155] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), andthe mixture was cooled to −10° C. Then, sodium ethoxide (102 mg, 1.5mmol) was added thereto and the mixture was stirred at the sametemperature for 0.5 hours. Then, 7-bromomethyl-2-naphthalenecarbonitrile (370 mg, 1.5 mmol) was gradually added thereto, theresultant mixture was stirred at the same temperature for 3 hours. Afterthat, procedures of Example 37 were repeated. Analysis by reversed-phasechromatography by use of the obtained product from Example 36 as astandard sample revealed that 332 mg of the title compound was obtained(44% yield).

Example 42 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0156] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), andthe mixture was cooled to −10° C. Then, sodium amide (60 mg, 1.5 mmol)was added thereto and the mixture was stirred at the same temperaturefor 0.5 hours. Then, 7-bromomethyl-2-naphthalene carbonitrile (370 mg,1.5 mmol) was gradually added thereto, the resultant mixture was stirredat the same temperature for 2 hours. After that, procedures of Example37 were repeated. Analysis by reversed-phase chromatography by use ofthe obtained product from Example 36 as a standard sample revealed that158 mg of the title compound was obtained (21% yield).

Example 43 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0157] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (500 mg, 1.5 mmol) and 7-chloromethyl-2-naphthalene carbonitrile(363 mg, 1.8 mmol) were dissolved in dimethylformamide(5 ml), and themixture was cooled to 0° C. Then, 60% sodium hydride (66 mg, 1.65 mmol)was added thereto and the mixture was stirred at the same temperaturefor 3 hours. After that, procedures of Example 37 were repeated.Analysis by reversed-phase chromatography by use of the obtained productfrom Example 36 as a standard sample revealed that 473 mg of the titlecompound was obtained (62% yield).

Example 44 Method for Preparing2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0158] 2-[4-[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenylacetic acid ethylester (5.4 g, 16 mmol, purity: 82%) and 7-bromomethyl-2-naphthalenecarbonitrile (4.7 g, 19.2 mmol) were dissolved in triethyleneglycoldimethyl ether (54 ml), and the mixture was cooled to 0° C. Then, 60%sodium hydride (704 mg, 17.6 mmol) was added thereto, and the mixturewas stirred at the same temperature for 8 hours. The resultant mixturewas diluted with acetic acid ethyl ester (108 ml), and was washed threetimes with water (216 ml). After concentration of the resultant organiclayer under reduced pressure, analysis by reversed-phase chromatographyby use of the obtained product from Example 36 as a standard samplerevealed that 6.4 g of the title compound was obtained (79% yield).

Example 45 Method for Preparing(2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0159]2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (54.1 g, 0.11 mol, purity: 66%) obtained from Example17 was heated and dissolved in ethanol (180 ml), and the resultantmixture was cooled to room temperature with stirring to settle crystals.Subsequently, sodium ethoxide (1.1 g, 15.8 mmol) was added thereto,followed by stirring at the same temperature for 30 minutes, then sodiumethoxide (1.1 g, 15.8 mmol) was further added, followed by stirring for18 hours. The crystals were collected through filtration, and washedwith ethanol (55 ml). The crystals were found to have a diastereomerpurity of 94.7% under HPLC analysis conditions of Reference Example 49described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.The crystals were dissolved in acetic acid ethyl ester (1228 ml), andwashed three times with water (250 ml). The resultant organic layer wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol (550 ml) to obtain 47.6 g of the title compound (88%yield). The data measured by instruments agreed with the data ofReference Example 49 described in Japanese Patent Application Laid-Open(kokai) No. 5-208946. The diastereomer purity of the crystals was 99.5%.

Example 46 Method for Preparing(2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0160]2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (50.0 g, 0.10 mol, purity: 67%) obtained from Example18 was heated and dissolved in ethanol (165 ml), and the resultantsolution was cooled to room temperature with stirring to settlecrystals. Subsequently, sodium ethoxide (1.0 g, 14.6 mmol) was addedthereto, followed by stirring at the same temperature for 30 minutes,then sodium ethoxide (1.0 g, 14.6 mmol) was further added, followed bystirring for 18 hours. The crystals were collected through filtration,and washed with ethanol (50 ml). The crystals were found to have adiastereomer purity of 93.5%. The crystals were dissolved in acetic acidethyl ester (1900 ml), and washed three times with water (240 ml). Theorganic layer was concentrated under reduced pressure, and the residuewas recrystallized from ethanol (500 ml) to obtain 43.8 g of the titlecompound (88% yield). The diastereomer purity of the crystals was 99.6%.

Example 47 Method for Preparing(2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0161]2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (11.3 g, 21.9 mmol, purity: 61%) obtained from Example29 was heated and dissolved in ethanol (40 ml), and the resultantsolution was cooled to room temperature with stirring to settlecrystals. Subsequently, sodium ethoxide (235 mg, 3.28 mmol) was addedthereto, followed by stirring at the same temperature for 30 minutes,then sodium ethoxide (235 mg, 3.28 mmol) was further added, and followedby stirring for 18 hours. The crystals were collected throughfiltration, and were washed with ethanol (10 ml). The obtained crystalshad a diastereomer purity of 92.8%. The crystals were dissolved inacetic acid ethyl ester (250 ml), and washed three times with water (50ml). The resultant organic layer was concentrated under reducedpressure, and the residue was recrystallized twice from ethanol (120 ml,100 ml) to obtain 9.23 g of the title compound (82% yield). Thediastereomer purity of the crystals was 99.8%.

Example 48 Method for Preparing(2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0162]2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (1.90 g, 3.7 mmol) was heated and dissolved in ethanol(6 ml), and the resultant solution was cooled to room temperature withstirring to settle crystals. Subsequently, sodium amide (22 mg, 0.6mmol) was added thereto, followed by stirring at the same temperaturefor 30 minutes, then sodium amide (22 mg, 0.6 mmol) was further added,followed by stirring for 18 hours. The crystals were collected throughfiltration to obtain 1.48 g of the title compound (78% yield). Thediastereomer purity of the crystals was 92.3%.

Example 49 Method for Preparing(2S)-2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0163]2-[4-[[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (25ml), and the resultant solution was cooled to room temperature withstirring to settle crystals. Subsequently, sodium ethoxide (100 mg, 1.5mmol) was added thereto, followed by stirring at the same temperaturefor one hour, then sodium ethoxide (100 mg, 1.5 mmol) was further added,followed by stirring for 15 hours. The crystals were collected throughfiltration to obtain 3.3 g of the title compound (66% yield). Theobtained crystals had a diastereomer purity of 82% under HPLC analysisconditions. The crystals were dissolved in acetic acid ethyl ester (75ml), and washed three times with water (50 ml). The resultant organiclayer was concentrated under reduced pressure, and the residue wasrecrystallized twice from ethanol (31 ml, 23 ml) to obtain 2.1 g of thetitle compound (43% yield). The diastereomer purity of the crystals was99.1%.

[0164] Melting point: 95.0 to 95.5° C.

[0165] Nuclear Magnetic Resonance Spectrum (CDCl₃) δ: 1.10 (3 H, t,J=6.9 Hz), 1.98 (1 H, m), 2.28 (1 H, m), 2.60 (1 H, m) 2.74 (2 H, m),2.98 (1 H, dd, J=6.9, 8.6 Hz), 3.16 (1 H, dd, J=6.9, 13.5 Hz), 3.54 (1H, dd, J=8.6, 13.5 Hz), 3.67 (2 H, dd, J=12.9, 12.9 Hz), 3.85 (1 H, dd,J=6.9, 8.6 Hz), 3.96-4.12 (2 H, m), 4.79 (1 H, m), 6.76 (2 H, d, J=8.6Hz), 7.19 (2 H, d, J=8.9 Hz), 7.24-7.35 (5H, m), 7.41 (1 H, dd, J=8.3,8.6 Hz), 7.54 (1 H, dd, J=8.3, 8.6 Hz), 7.60 (H, s), 7.71 (1 H, d, J=8.6Hz), 7.84 (1 H, d, J=8.6 Hz), 8.11 (1 H, s)

[0166] Elementary Analysis C₃₃H₃₂N₂O₄:

[0167] Calculated: C, 78.55; H, 6.39; N, 5.55 Found: C, 78.40; H, 6.48;N, 5.35

[0168] MS (m/Z): 504(M⁺) Infrared Absorption Spectrum νmax (KBr) cm⁻¹:2800, 2232, 1730, 1610, 1512, 1254, 1156, 850

[0169] Angle of Rotation [α]²²D=+112.5° (c=1.0, CHCl₃)

Example 50 Method for Preparing(2S)-2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0170]2-[4-[[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (50ml), and the resultant solution was cooled to room temperature withstirring to settle crystals. Subsequently, sodium ethoxide (100 mg, 1.5mmol) was added thereto, followed by stirring at the same temperaturefor one hour, then sodium ethoxide (100 mg, 1.5 mmol) was further added,followed by stirring for 15 hours. The crystals were collected throughfiltration to obtain 2.9 g of the title compound (58% yield). Thecrystals had a diastereomer purity of 84% under HPLC analysisconditions. The crystals were dissolved in acetic acid ethyl ester (66ml), and washed three times with water (50 ml). The resultant organiclayer was concentrated under reduced pressure, and the residue wasrecrystallized twice from ethanol (14.5 ml, 12 ml) to obtain 2.0 g ofthe title compound (40% yield). The diastereomer purity of the crystalswas 93%.

Example 51 Method for Preparing(2S)-2-[4-[[(3S)-1-benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester

[0171]2-[4-[[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionicacid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (15ml), and the resultant solution was cooled to room temperature withstirring to settle crystals. Subsequently, sodium ethoxide (100 mg, 1.5mmol) was added thereto, followed by stirring at the same temperaturefor one hour, then sodium ethoxide (100 mg, 1.5 mmol) was further added,followed by stirring for 15 hours. The crystals were collected throughfiltration to obtain 3.9 g of the title compound (77% yield). Theobtained crystals had a diastereomer purity of 47% under HPLC analysisconditions.

[0172] Industrial Applicability

[0173] The present invention provides a process for preparing2-phenyl-3-naphthylpropionic acid derivatives and optically activecompounds thereof which play important roles as intermediates inmanufacturing aromatic amidine derivatives having anticoagulation actionbased on excellent activated coagulation factor X. The process of thepresent invention is not only operationally simpler, but also costlyadvantageous. Thus, the process of the present invention isoperationally and economically satisfactory as a useful process forindustrial manufacture.

1. A process for preparing a compound of formula (III) or a salt thereof:

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] characterized by reacting a compound represented by formula (I):

[wherein R¹ has the same meaning as defined above and R² represents a methanesulfonyl group or p-toluenesulfonyl group] with a compound represented by formula (II):

[wherein R³ has the same meaning as defined above] in the presence of a base.
 2. A process for preparing a compound of formula (IIIa) or a salt thereof:

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] characterized by reacting a compound represented by formula (Ia):

[wherein R¹ has the same meaning as defined above and R² represents a methanesulfonyl group or p-toluenesulfonyl group] with a compound represented by formula (II):

[wherein R³ has the same meaning as defined above] in the presence of a base.
 3. The process according to claim 1 or 2, wherein the reaction is performed in the presence of a catalyst.
 4. The process according to claim 3, wherein the catalyst is a phase-transfer catalyst.
 5. The process according to claim 3 or 4, wherein the catalyst is an oleophilic quaternary ammonium salt.
 6. The process according to any one of claims 3 through 5, wherein the catalyst is tetra(n-butyl)ammonium bromide.
 7. The process according to any one of claims 1 through 6, wherein the base is a strong base.
 8. The process according to any one of claims 1 through 7, wherein the base is alkali metal hydride.
 9. The process according to any one of claims 1 through 8, wherein the base is sodium hydride.
 10. The process according to any one of claims 1 through 9, wherein the reaction is performed in an aromatic hydrocarbon.
 11. The process according to any one of claims 1 through 10, wherein the reaction is performed in toluene.
 12. A process for preparing a compound of formula (IVa)

[wherein X² is a halogen atom] characterized by halogenation of a compound of formula (VII):

in an alkylnitrile solvent.
 13. The process according to claim 12, wherein the halogenation is performed in the presence of a radical initiator.
 14. The process according to claim 12 or 13, wherein the alkylnitrile solvent is acetonitrile.
 15. The process according to any one of claims 12 through 14, wherein the halogenation is performed by the addition of a halogenating agent.
 16. The process according to claim 15, wherein the halogenating agent is N-bromosuccinimide.
 17. The process according to any one of claims 12 through 16, wherein the radical initiator is 2,2′-azobisisobutyronitrile.
 18. A process for preparing a compound of formula (V) or a salt thereof:

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] characterized by reacting a compound represented by formula (III):

[wherein R¹ and R³ have the same meanings as defined above] with a compound represented by formula (IV):

[wherein X¹ is a leaving group] in the presence of a base.
 19. A process for preparing a compound of formula (Va) or a salt thereof:

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] characterized by reacting a compound represented by formula (IIIa):

[wherein R¹ and R³ have the same meanings as defined above] with a compound represented by formula (IV):

[wherein X¹ is a leaving group] in the presence of a base.
 20. The process according to claim 18 or 19, wherein the base is a strong base.
 21. The process according to any one of claims 18 through 20, wherein the base is alkali metal hydride.
 22. The process according to any one of claims 18 through 21, wherein the base is sodium hydride.
 23. The process according to any one of claims 18 through 22, wherein the reaction is performed in a solvent mixture of an aprotic polar solvent and an aromatic hydrocarbon.
 24. The process according to any one of claims 18 through 23, wherein the reaction is performed in a solvent mixture of N,N-dimethylformamide and toluene.
 25. The process according to any one of claims 18 or 20 through 24, wherein the compound of formula (III) is obtained by the process as described in any one of claims 1 or 3 through
 11. 26. The process according to any one of claims 19 through 24, wherein the compound of formula (IIIa) is obtained by the process as described in any one of claims 2 through
 11. 27. The process according to any one of claims 18 through 26, wherein the compound of formula (IV) is a compound represented by formula (IVa):

[wherein X² is a halogen atom].
 28. The process according to claim 27, wherein the compound of formula (IVa) is obtained by the process as described in any one of claims 12 through
 17. 29. The process according to claim 27 or 28, wherein the reaction between a compound of formula (IVa) and a compound of formula (III) is performed in a solvent mixture of an aromatic hydrocarbon and an aprotic polar solvent, and the aromatic hydrocarbon is an extraction solvent for taking up the compound of formula (IVa) from the reaction mixture which has undergone halogenation reaction.
 30. The process according to claim 29, wherein the aromatic hydrocarbon is toluene.
 31. The process according to claim 29, wherein the solvent mixture of an aprotic polar solvent and an aromatic hydrocarbon is a mixture of N,N-dimethylformamide and toluene.
 32. A process for producing a compound represented by formula (Vb):

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] characterized by reacting a compound represented by formula (Va):

[wherein R¹ and R³ have the same meanings as defined above] with a base.
 33. The process according to claim 32, wherein the base is alkali metal alkoxide.
 34. The process according to claim 32 or 33, wherein the base is sodium ethoxide.
 35. The process according to any one of claims 32 through 34, wherein the reaction is performed in a protic solvent.
 36. The process according to any one of claims 32 through 35, wherein the reaction is performed in an alcohol.
 37. The process according to any one of claims 32 through 36, wherein the reaction is performed in ethanol.
 38. The process according to any one of claims 32 through 37, wherein the compound of formula (Va) is obtained by the process as described in any one of claims 19 through
 31. 39. The process according to any one of claims 32 through 38, wherein R¹ is an alkyl group having 1 to 6 carbon atoms.
 40. The process according to any one of claims 32 through 39, wherein R¹ is an ethyl group.
 41. The process according to any one of claims 32 through 40, wherein R² is tert-butoxycarbonyl group.
 42. A process for preparing (2S)-2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester, characterized by reacting 2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester with sodium ethoxide in ethanol.
 43. A compound represented by formula (III)

[wherein R¹ represents a protective group for a nitrogen atom and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] or a salt thereof.
 44. A compound represented by formula (IIIa)

[wherein R¹ represents a protective for a nitrogen atom group and R³ represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms] or a salt thereof.
 45. A compound represented by formula (Vc)

[wherein R^(1c) represents a tertiary butoxycarbonyl group and R^(3c) represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms (other than an ethyl group)], or a salt thereof.
 46. A compound represented by formula (Vd)

[wherein R^(1d) represents a benzyl group and R^(3d) represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms], or a salt thereof. 